Evolution and improved outcomes in the era of multimodality treatment for extended pancreatectomy

Abstract Background The evolution and outcomes of extended pancreatectomies at a single institute over 15 years are presented in this study. Methods A retrospective analysis of the institutional database was performed from 2015 to 2022 (period B). Patients undergoing extended pancreatic resections, as defined by the International Study Group for Pancreatic Surgery, were included. Perioperative and survival outcomes were compared with data from 2007–2015 (period A). Regression analyses were used to identify factors affecting postoperative and long-term survival outcomes. Results A total of 197 (16.1%) patients underwent an extended resection in period B compared to 63 (9.2%) in period A. Higher proportions of borderline resectable (5 (18.5%) versus 51 (47.7%), P = 0.011) and locally advanced tumours (1 (3.7%) versus 24 (22.4%), P < 0.001) were resected in period B with more frequent use of neoadjuvant therapy (6 (22.2%) versus 79 (73.8%), P < 0.001). Perioperative mortality (4 (6.0%) versus 12 (6.1%), P = 0.81) and morbidity (23 (36.5%) versus 83 (42.1%), P = 0.57) rates were comparable. The overall survival for patients with pancreatic adenocarcinoma was similar in both periods (17.5 (95% c.i. 6.77 to 28.22) versus 18.3 (95% c.i. 7.91 to 28.68) months, P = 0.958). Resectable, node-positive tumours had a longer disease-free survival (DFS) in period B (5.81 (95% c.i. 1.73 to 9.89) versus 14.03 (95% c.i. 5.7 to 22.35) months, P = 0.018). Conclusion Increasingly complex pancreatic resections were performed with consistent perioperative outcomes and improved DFS compared to the earlier period. A graduated approach to escalating surgical complexity, multimodality treatment, and judicious patient selection enables the resection of advanced pancreatic tumours.


Introduction
Complete surgical resection is the most critical predictor in achieving long-term survival in localized pancreatic adenocarcinoma (PDAC) [1][2][3][4][5] .A majority of PDACs are either borderline resectable (BR) or locally advanced (LA) due to frequent vascular involvement, posing a challenge for a margin-negative resection.From its initial description by Fortner in 1973 6 , portal vein resections have now become a standard of care for the surgical resection of advanced pancreatic cancers [7][8][9][10] .With improved surgical techniques and more effective systemic therapy 11,12 , more aggressive resections involving major arteries have been made possible, leading to improved survival in a select group of patients [13][14][15][16][17][18][19][20] .Pancreatic resections involving additional resection of vascular structures and adjacent organs are associated with higher perioperative mortality and morbidity compared to standard pancreatic resections 21 .Hartwig et al.  streamlined the definition of extended pancreatic resections in a consensus statement of the international study group of pancreatic surgery (ISGPS) in 2014 22 .A previous study of 63 cases of extended pancreatic resections was performed over 9 years (2007-2015), and it found a postoperative mortality rate of 6% and a major morbidity rate of 67% 21 .
The practice at Tata Memorial Centre has evolved over the years in tandem with other high-volume pancreatic surgery centres worldwide.Over the last decade, it has seen progressively higher volumes, more complex resections, and increased utilization of neoadjuvant therapy (NAT).In the present study, the aim was to assess the impact of this evolution over time.

Study design
A prospectively maintained institutional database of pancreatic resections was analysed.Patients who underwent an extended pancreatic resection between 1 September 2015 and 31 August 2022 were included in the study.This period was designated as 'period B'.Extended resections were defined by the ISGPS https://doi.org/10.1093/bjsopen/zrae065Original Article criteria 22 as pancreatic resections with additional resection of adjacent organs, vascular resections, or extended lymph node dissection.Perioperative, pathologic and survival outcomes were assessed.Perioperative mortality, perioperative morbidity, ideal outcomes, failure-to-rescue rate, margin positive (R+) rate, DFS, and overall survival (OS) for period B were compared to previously published results from an earlier period (January 2006 to August 2015), which was designated as 'period A' 21 .
Resectability criteria were assessed by the National Comprehensive Cancer Network (NCCN) guidelines 23 .Perioperative mortality included death from any cause within 90 days from the date of surgery.A complication classified as Clavien-Dindo grade IIIa or higher was defined as major morbidity 24 .Ideal outcomes for pancreatic surgery were defined by the absence of in-hospital mortality, major morbidity, postoperative pancreatic fistula (POPF) grade B or C, re-exploration, readmission and hospital stay > 75th percentile 25 .The 75th percentile of hospital stay was derived from the entire institutional cohort of pancreatic surgeries.Postoperative complications such as a POPF, biliary leak, post-pancreatectomy haemorrhage (PPH), chyle leak and delayed gastric emptying (DGE) were defined following the ISGPS criteria [26][27][28][29] .Surgical specimens were analysed by multiple pathologists and the margin status was reported by the standardized LEEDS pathology protocol 30 .Pathologic tumour response was reported according to the College of American Pathologists (CAP) protocol 31 .
Survival outcomes were analysed only for PDAC.DFS was the period from the date of surgery to the date of recurrence or the date of last follow-up.OS was the period from the date of diagnosis to death from any cause or the date of last follow-up.The failure-to-rescue rate was the ratio of patients who died within 90 days of surgery to those who suffered major morbidity, expressed as a percentage 32 .

Treatment planning
Response assessment to chemotherapy was based on radiological, biochemical and patient-related subjective criteria.Borderline resectable pancreatic cancer (BRPC) patients with no or limited (<180 degrees with a single artery) arterial contact and a favourable response after four chemotherapy cycles were planned for surgical resection after an additional 2-4 chemotherapy cycles.BRPC with significant arterial contact (>180 degrees), contact with multiple arteries, and locally advanced pancreatic cancer (LAPC) patients were planned for a total neoadjuvant therapy (TNT), defined as completion of ≥ 6 cycles of neoadjuvant chemotherapy (NACT) 33 , with an aim to complete 10-12 cycles before surgery.LAPCs and BRPCs with arterial involvement were considered for stereotactic body radiotherapy (SBRT).The routine follow-up schedule consisted of in-person visits to the outpatient clinic every 3 months for the first 2 years after surgery and every 6 months for the following 3 years.'Recurrence' was documented upon obtaining tissue diagnosis of suspicious lesions, unless the radiology and tumour marker profile was definitive enough to obviate the need for a tissue diagnosis.

Statistical analysis
Categorical variables were expressed as proportions, whereas continuous variables were expressed as median and range.Categorical variables were compared using a Pearson Chi-square test, and continuous variables were compared using a Mann-Whitney/U-test. Factors impacting mortality and morbidity were analysed by a stepwise binomial logistic regression.Patient age, sex, ASA grade, BMI, tumour size, preoperative biliary stenting, preoperative albumin level, NAT, type of pancreatectomy, the complexity of surgery, number of additional organs resected, intraoperative blood loss and duration of surgery were the variables analysed in a stepwise multivariate regression to predict postoperative mortality (90-day) and morbidity.Receiver operating characteristic (ROC) curves were plotted for continuous variables identified as significant predictors of postoperative mortality, and the area under ROC (AUC) was analysed.The median duration of follow-up was assessed by using the reverse Kaplan-Meier method.Survival outcomes were plotted using Kaplan-Meier curves and were compared using a log-rank test.Factors impacting long-term survival were analysed by using a stepwise Cox regression.P ≤ 0.05 was considered statistically significant.This study was performed in accordance with ethical guidelines laid out in the Helsinki Declaration (2008) and after obtaining approval from the institutional ethics committee
Staging laparoscopy was used selectively in patients with elevated carbohydrate antigen (CA 19-9 levels).A superior mesenteric artery (SMA)-first approach was utilized in all cases.End-to-end reconstruction was the preferred venous or arterial reconstruction approach after segmental resection.A saphenous vein graft was used for arterial reconstruction if end-to-end reconstruction was not feasible.A polytetrafluoroethylene (PTFE) graft was used if a suitable autologous graft could not be obtained.Local application of heparinized saline during venous resections or a bolus dose of 5000 units of unfractionated heparin for arterial reconstructions were used.Postoperative anticoagulation with continuous heparin infusion was not implemented.Drains were placed in all patients and were removed between postoperative days 5 and 7 during an uneventful recovery.The clinical and surgical details are shown in Table 1.
Combined venous and multivisceral resections (HR 13.25), arterial resection or divestment procedures (HR 2.313), intraoperative blood loss (HR 1.00) and duration of surgery (HR 0.996) were identified as independent predictors of major morbidity.Regression output for perioperative outcomes was provided in Table 3, and ROC curves in Fig. 2.
Survival outcomes were analysed for PDAC only.The median duration of follow-up for PDAC was equivalent in both periods (    3. None of the clinicopathological variables assessed was identified as an independent predictor of long-term survival on multivariate Cox regression.Details of the Cox regression have been elaborated in Table S1.

Subgroup analysis
Survival outcomes of the subgroup of resectable PDACs were compared between the two time periods.All relevant clinicopathological characteristics were evenly matched between the two periods except lymph node yield, which was significantly higher in period B (median lymph node yield 11 versus 21 nodes, P = 0.045).Clinicopathological characteristics of the resectable PDAC subgroup have been summarized in Table S2.
The median DFS of isolated vein resections in period B was significantly longer than period A (9.49 (95% c.i. 6.24 to 12.75) versus 13.14 (95% c.i. 9.36 to 16.91) months, P = 0.028), with an estimated 2-year DFS of 0% and 30.5% in periods A and B, respectively.The survival curves are depicted in Fig. S1.

Discussion
Significantly greater numbers of extended pancreatic resections were undertaken in period B, along with a foray into more complex arterial resection and divestment procedures and more frequent and prolonged use of NAT.Despite a significant increase in the complexity of surgery, surgical outcomes remained unchanged between the two periods.Four independent risk factors for perioperative mortality were identified: age, intraoperative blood loss, duration of surgery and preoperative albumin.Long-term survival remained unchanged between the two periods.A significantly longer DFS was observed in the subgroup of node-positive resectable pancreatic cancers, likely attributable to more radical surgery as evidenced by a higher lymph node yield in period B. DFS was significantly longer in the 'vein resection only' subgroup in period B as well.
Augustinus et al. 25 defined the criteria for ideal outcomes in pancreatic surgery in a sizeable transatlantic cohort study comprising 21 036 patients from North America, Germany, the Netherlands and Sweden.In their study, ideal outcomes were reached in 54% of patients.The results from the present analysis are comparable, with 128 (49.2%) patients reaching ideal outcomes.A closer look at the factors affecting perioperative outcomes identified four independent risk factors for perioperative mortality: age, intraoperative blood loss, duration of surgery and preoperative albumin.Patient age, an unmodifiable risk factor, should influence patient selection while considering patients for an extended pancreatic resection.Patient age of more than 58.5 years predicted mortality with a sensitivity and specificity of 80% and 58.8%, indicating a need for more stringent evaluation of patients > 60 years.This age cut-off may seem more conservative as far as pancreatic surgery is concerned.Although the safety and oncological benefit of a pancreatoduodenectomy has been demonstrated in a geriatric population 43 , one must emphasize that this benefit was restricted to patients with resectable periampullary malignancies undergoing standard pancreatic resections, as well as the fact that the current average life expectancy in India is only 70.4 years 44 .The remaining three factors, namely preoperative albumin, intraoperative blood loss and duration of surgery, are modifiable risk factors that serve to reiterate the core principles underlining improved surgical outcomes: careful patient selection, aggressive preoperative optimization, and meticulous surgical technique.Interestingly, the complexity of surgery was not independently associated with surgical mortality but only with morbidity, indicating that although increasingly complex resections are associated with higher complication rates, salvaging those complications in the postoperative period is the key to reducing the perioperative mortality rate.
In the earlier publication, extended pancreatic resections for PDAC were also associated with a significantly poorer DFS of 9.5 months as compared to 19.5 months with standard pancreatectomies, which was attributed to a high margin

Fig. 1
Fig. 1 Consort diagram of the study population

Table 1 Demographic, clinical and treatment characteristics of extended pancreatic resections
equivalent (8.6 (95% c.i. 3.88 to 13.32 versus 10.67 (95% c.i. 8.52 to 12.82) months, P = 509) with an estimated 3-year DFS of 22.5% and 20.9% in periods A and B respectively.The median OS of PDAC in both periods was equivalent (17.5 (95% c.i. 6.77 to 28.22) versus 18.3 (95% c.i. 7.91 to 28.68) months, P = 0.958) with an estimated 3-year OS of 43.5% and 30.6% in periods A and B respectively.The survival curves of PDAC in period B are shown in Fig.

Table 2 Perioperative outcomes of extended pancreatic resections
21atistically significant difference.†Denominatorcomprisingtotal multivisceral resections in the respective time period.‡Denominatorcomprisingtotal vascular resections in the respective time period.§Denominatorcomprisingtotal combined resections in the respective time period.¶Denominatorcomprisingtotal number of each type of vascular resection in the respective time period.#Denominatorcomprisingtotal number of pancreatic adenocarcinomas (PDAC) in the respective time period.**Onepatient in period B underwent additional arterial divestment.positive(R+)rate of 40.7% at the time21.Limited use of neoadjuvant therapy (26%) in the study also failed to reflect the current practice standard for advanced pancreatic cancer comprising more aggressive and prolonged neoadjuvant chemotherapy regimens.The median DFS and OS in period B were 11.72 months and 23.52 months respectively.Overall, the

Table 3 Logistic regression for factors affecting perioperative outcomes
DP, distal pancreatectomy; PD, pancreaticoduodenectomy; TP, total pancreatectomy.Fig. 2 ROC curves of factors predicting postoperative mortality a Patient age, intraoperative blood loss and duration of surgery; b preoperative albumin Chaudhari et al. | 7difference was not statistically significant between the two periods.However, despite similar R0 resection rates, a significantly longer DFS was observed in the subgroup of node-positive resectable pancreatic cancers, likely attributable to more radical surgery as evidenced by a higher lymph node yield in period B. DFS was significantly longer in the 'vein resection only' subgroup in period B as well.In period B, NAT was utilized more frequently with more radical resections, as